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Manufacturing: the next breakthrough in gene therapy

By Diane Blumenthal

December 18, 2019

Spark Therapeutics manufacturing associates preparing to purify Luxturna at the company's manufacturing facility in West Philadelphia, Pennsylvania.
Spark Therapeutics manufacturing associates preparing to purify Luxturna at the company's manufacturing facility in West Philadelphia, Pennsylvania.

I never thought I’d see the day when words like “process,” “scale,” and “automation” would make news in the biopharma industry. Yet as the race heats up to bring more first-of-their-kind gene therapies to market, breakthroughs in manufacturing are often the key — or break down the barrier — to delivering these therapies to patients.

In my career, which has largely focused on drug manufacturing, I’ve been lucky to be directly involved in the approval of six new medicines. My current work, as head of technical operations at Spark Therapeutics, is offering the biggest challenge: bringing Luxturna, the first gene therapy for a genetic disease, to patients and families in the U.S. Getting here has been no small task.

With no precedent to guide us, we had to forge new clinical, regulatory, and manufacturing pathways. Working through the unknown meant developing a robust set of assays to test various aspects of the gene therapy product just so we could better understand it. We also built, from scratch, the only in-house manufacturing facility for a licensed gene therapy that is approved by both the U.S. Food and Drug Administration and the European Medicines Agency. This facility is located on the 13th floor of a high-rise in West Philadelphia.

Gene therapy, as others in this space know, is not a one-size-fits-all approach. That means there isn’t a gene therapy manufacturing playbook — yet — to guide the development of gene therapies, as there is for well-established therapeutic categories. And at least for now, every gene therapy is different. Each relies on a different delivery mechanism (vector) to transport functional copies of a gene into the patient.

Even if one day we have a platform that is flexible enough to accommodate multiple vector types, we’ll still need to consider the fact that individual therapies require different dosing and modes of administration, both dependent on the patient’s cells and disease. While we certainly seek to standardize processes through enhanced analytics, automation, and even artificial intelligence, manufacturing each therapy will still require custom processes.

And time is of the essence, because patients and their families are waiting for these therapies. Given that many of these diseases have limited or no treatment options, regulatory authorities are rightly granting expedited approval pathways for investigational gene therapies. The tight timelines in these pathways narrow the window for manufacturing teams to plan and implement strategies to create gene therapies at scale for commercial use.

Here are three aspects I see as unique to the gene therapy manufacturing process:

Get comfortable with the uncomfortable. Given the shortened clinical development timelines and limited precedent to guide them, gene therapy manufacturers must make decisions about investing in Phase 3 manufacturing processes far in advance of knowing the clinical outcome of their therapy. It’s important to trust your expertise and invest in well informed “good risk.” We saw the success of this at Spark with the first gene therapy, which is helping create a clearer road map for future ones.

Develop capability for capacity. Manufacturing a gene therapy is only half the battle. The other half is making enough of it, doing that as efficiently as possible, and getting it to the patients who need it. These challenges become even more urgent to tackle as the industry shifts to the next chapter in gene therapy development, from treatments made in small batches for small patient populations to bigger volumes for larger rare-disease populations and commercial scale.

Spark, for example, is optimizing the way it produces viral vectors, shifting from adherent cell lines, which attach cells to the sides of roller bottles, to a suspension process that is more efficient and scalable. In this process, bioreactors grow cells unattached, in a liquid or suspended environment. This alternate way of manufacturing uses well-established unit operations commonly employed in the biotechnology industry, making efficiency at scale more easily achievable. Less manual manipulation provides for more process consistency and higher success rates. Each of these elements aids in our ability to scale more easily.

Don’t let perfection be the enemy of progress. Versions of this phrase have been attributed to Voltaire, Shakespeare, and Winston Churchill, among others, but the point here is that when it comes to manufacturing, the process is never perfect and can always be better. Our gene therapy manufacturing processes are constantly evolving based on what we learn from them and from new best practices. What matters most today is that we can manufacture gene therapies safely and effectively. The speed will continue to improve.

Manufacturers are accustomed to setting up highly repeatable processes for making and delivering medicines. But when it comes to gene therapies, we understand that the ingenuity for manufacturing needs to be as unique and cutting-edge as the therapies themselves.

While it’s exciting to see gene therapy manufacturing in the limelight today, I hope that the progress we are making will soon make these challenges old news.


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